1. Field of the Disclosure
The disclosure relates generally to methods of preparing sevoflurane (1,1,1,3,3,3-hexafluoro-2-(fluoromethoxy)propane). More particularly, the disclosure is directed to the synthesis of sevoflurane from the reaction of chlorosevo ether (1,1,1,3,3,3-hexafluoro-2-(chloromethoxy)propane) and a nucleophilic fluoride reagent, using the desired end-product of sevoflurane as a solvent.
2. Brief Description of Related Technology
Sevoflurane is a halogenated, volatile anesthetic typically administered by inhalation to induce and/or maintain general anesthesia. U.S. Pat. No. 5,886,239 describes a process for synthesizing sevoflurane involving the fluorination of chlorosevo ether with an amine hydrofluoride salt. The '239 patent discloses that a molar excess of the precursor chlorosevo ether can be included in the reaction to act as a solvent (column 3, lines 38-42). In Example 1, a 0.5 molar excess of chlorosevo ether (corresponding to an initial reaction mixture containing 1.5 molar equivalents of chlorosevo ether relative to 1.0 molar equivalent of HF) is used in the synthesis to yield an organic layer containing 63.6% sevoflurane and 35.4% chlorosevo ether. While a 95% conversion yield of sevoflurane (based on the starting material consumed) is achieved in the exemplified synthesis, it is necessary for the remaining, unreacted, excess chlorosevo ether, which is a valuable precursor reagent, to be recovered and purified so that it may be reused in subsequent reactions.
Additionally, the synthesis of sevoflurane from excess chlorosevo ether and a nucleophilic fluoride reagent has been found to yield other impurities such as hexafluoroisopropanol (HFIP), sevomethyl ether (SME), and high boiling oligomeric products derived from chlorosevo ether.
Since sevoflurane should be substantially free from impurities for use in pharmaceutical applications, improved methods for producing sevoflurane are desirable, particularly methods that provide sevoflurane at a higher purity and/or simplify the processing of the reaction product while increasing or maintaining the conversion yields achieved in the '239 patent.